N-6 cyclopropylPMEDAP (“cpr-PMEDAP”) has been shown to be effective producing an antiproliferative and differentiation-inducing effect in in vitro cell culture against a variety of tumor cell lines (Naessens et al., “Biochem. Pharmacol. 1999 Jul. 15; 58(2):311-23). However, when cpr-PMEDAP and other N6-substituted. PMEDAP compounds were employed in an in vivo model of haematological malignancy of inbred Sprague-Dawley rats (Valerianova et al. “Anticancer Res. 2001 May-June; 21(3B):2057-64), the authors concluded that the “acyclic nucleoside phosphonates substituted at the 6-position of 2,6-diaminepurine ring do not seem to be promising drugs for the treatment of haematological malignancies” due to “high toxicity”.
Various bis- and mono-amino acid amidate esters of cpr-PMEDAP (and their use as antiproliferative agents) have been disclosed. See WO 05/066189. WO 02/08241 discloses a method for screening methoxyphosphonate nucleotide analogue prodrugs that are useful for treating hematological malignancies with reduced toxicity.
Hematological malignancies are broadly defined as proliferative disorders of blood cells and/or their progenitors, in which these cells proliferate in an uncontrolled manner. Anatomically, the hematologic malignancies are divided into two primary groups: lymphomas—malignant masses of lymphoid cells, primarily but not exclusively in lymph nodes, and leukemias—neoplasm derived typically from lymphoid or myeloid cells and primarily affecting the bone marrow and peripheral blood. The lymphomas can be sub-divided into Hodgkin's Disease and Non-Hodgkin's lymphoma (NHL). The later group comprises several distinct entities, which can be distinguished clinically (e.g. aggressive lymphoma, indolent lymphoma), histologically (e.g. follicular lymphoma, mantle cell lymphoma) or based on the origin of the malignant cell (e.g. B lymphocyte, T lymphocyte). Leukemias and related malignancies include acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). Other hematological malignancies include the plasma cell dyscrasias including multiple myeloma, and the myelodysplastic syndromes.
While the introduction of novel agents such as imatinib (Gleevec®), bortezomib (Velcade®) and rituximab (Rituxin®) has improved the outcome of several hematological malignancies, there remains an unmet medical need for novel, efficacious therapeutics. For example, there is an unmet medical need for patients suffering from treatment-refractory/relapsed NHL, as the incidence of NHL has risen substantially in the United States over the past five decades.
Leukemias have lower patient numbers. However, there remains substantial unmet medical need, for example for the treatment of acute myelogenous leukemia (AML) and chronic lymphocytic leukemia (CLL), as illustrated by poor 5-year survival rates.
There is a need for multi-specific or broadly active antimetabolic agents with an improved therapeutic window over existing treatment modalities, which can be used either as stand-alone monotherapy or in combination with other therapeutics. Most antimetabolites either interfere with enzymes involved in DNA synthesis, such as the enzymes concerned with thymidine or purine biosynthesis, and/or are incorporated into newly synthesized DNA. Nucleobase, nucleoside, and nucleotide analogs are an important class of effective cytotoxic drugs, and are widely used for the treatment of leukemias and lymphomas. Some of these agents, 5-fluorouracil, capecitabine, and especially gemcitabine, are also being used for the treatment of solid tumors. Three adenosine analogs, fludarabine, cladribine, and clofarabine, are indicated for CLL, hairy-cell leukemia, and pediatric ALL, respectively. The purine analog, pentostatin (2′-deoxycoformycin), an inhibitor of adenosine deaminase, has clinical activity against lymphoid malignancies. Nelarabine is a prodrug of the deoxyguanosine analogue ara-G, which is resistant to catabolism by purine nucleoside phosphorylase and has demonstrated activity against T-cell malignancies. Amongst the pyrimidine analogs, cytarabine (ara-C) has been evaluated; it is active in a number of hematologic malignancies and is one of the agents used in the treatment of acute myelogenous leukemia.
However, existing therapies have limitations with regard to, for example, safety, efficacy and ease of use. It is not uncommon for treatments to be successful initially, then have the hematological malignancies frequently relapse over time.
Therefore, there remains a need for novel nucleosides/nucleotides with an improved therapeutic window and/or complimentary utility over existing compounds in this class.
Applicants sought a compound suitable for the treatment of hematological malignancies with improved PK and loading, improved therapeutic window and/or lower drug resistance. In particular it was desired to identify a compound that would concentrate in blood cells, in particular PBMCs. Concentrating the compound in these target cells would be expected to widen the therapeutic window by reducing the exposure of the patient's other tissues to the compound.
WO 05/066189 discloses a compound having structure 1:

This invention relates to compound 1. It also relates to the diastereomer thereof in which the bis amino acid substituted on the phosphorus atom is an L amino acid, as well as such diasteromer substantially free of D amino acid.
Heretofore compounds of formula I have been employed as the free base. However, applicants determined that the free base is not commercially optimal for formulation into a dosage form because the free base is hygroscopic. Accordingly applicants sought a form of compound 1 which could facilitate manufacturing processes for therapeutic dosage forms.